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PubMed2006

Bivalent inhibitors of glutathione S-transferase: the effect of spacer length on isozyme selectivity.

Glutathione S-transferases (GSTs) are cytosolic enzymes that catalyze the conjugation of glutathione with a variety of exogenous and endogenous electrophiles. High affinity, isozyme-specific inhibitors of GST are required for use as pharmacological tools as well as potential therapeutics. The design of selective inhibitors is hindered due to the broad substrate binding capabilities of the GST enzymes. GSTs are dimeric enzymes, and therefore offer a unique discriminator for achieving inhibitor selectivity: the distance between binding sites on each monomer unit as a function of its quaternary organization. Bivalent analogs of the non-selective GST inhibitor ethacrynic acid were prepared, and selectivity for the GST A1-1 isozyme over GST P1-1 (IC50 values of 13.7 vs 1022 nM, respectively) was achieved through the optimization of the spacer length between the ethacrynic acid ligand domains.

Antineoplastic Agents↗

PubMed1977

Kinetic behavior of thallium in the rat. Accelerated elimination of thallium owing to treatment with potent diuretic agents.

1. In acute experiments anesthetized rats were treated with a subthreshold dose of 204Tl+, given intravenously in order to study the elimination kinetics of Tl+. Thallium disappeared from whole blood by means of two different half-lives (5 and 196 min, respectively), whereas VDbeta amounted to 1400 ml. The same kinetic parameters were found after chronic exposure to toxic amounts of Tl+. 2. After chronic exposure to thallium (10 or 30 ppm in the drinking water), the distribution of thallium over various organs proved non-specific. However, a pronounced accumulation was found in the renal medulla. 3. In view of the importance of the renal route in the elimination of Tl+ from the body and also because of the established accumulation of the toxic metal in the kidney, the influence of potent diuretic agents like furosemide and ethacrynic acid on the excretion of Tl+ was studied. The enhanced excretion of water and ions (Na+, K+, Cl-) was accompanied by a significantly accelerated excretion of thallium ions. High doses of ethacrynic acid (25 mg/kg) proved particularly powerful in this respect. Between the enhanced excretion of thallium and potassium ions a significant correlation was obvious, thus supporting the well-known similarity in the behaviour of these ions. The marked increase in renal elimination of thallium upon intensive diuretic treatment may be useful in the management of thallotoxicosis.

Animals↗

PubMed1975

Changes in urea clearance after a single dose of diuretics during water diuresis.

The action of various diuretics on the excretion fraction of urea (Curea/Ccr) was studied in 91 healthy volunteers under conditions of maintained maximal water diuresis. On the basis of previous data on transtubular transport or urea it should be expected that with an increase in the excretion fraction of water (V/Ccr) under the given experimental conditions we should find an increase in Curea/Ccr. After administration of polythiazide, which has a predominantly distal localisation of action in the nephron, Curea/Ccr did not change. After administration of chlorothiazide, furosemide and after i.v. administration of ethacrynic acid there was a marked increase in V/Ccr, ranging from 5.4 to 18%. Despite this there was no significant increase in Curea/Ccr. After i.v. administration of acetazolamide or oral administration of ethacrynic acid Curea/Ccr even showed a statistically significant decrease. These findings suggest that a decrease in proximal tubular reabsorption of water after administration of diuretics during maximal water diuresis is not a decisive factor for the renal excretion of urea. The data suggest that the diuretics affected the permeability of the distal segment of the nephron for urea in the sense of an increase of tubular reabsorption.

Acetazolamide↗

PubMedDate not supplied

[Diuretic binding with biological membranes studied by means of a fluorescent probe].

The binding of furosemide, novurit and ethacrynic acid with human serum albumin, phospholipid liposomes, mitochondria and plasmatic membranes of rat kidneys was studied by the fluorescent probe 1-anilino naphthalene-8-sulfonate (1,8-ANS) method. It is shown that ethacrynic acid has high associative constants with serum albumin molecule and plasmatic membranes. Novurit has the greatest affinity with rat kidney mitochondria. Furosemide does not bind with plasmatic membranes and has very low constants of association with mitochondria and phospholipid liposomes.

Alkylmercury Compounds↗

PubMed2002

Solutol and cremophor products as new additives in suppository formulation.

Our research has a double purpose. On the one hand, doctors have expressed the need to formulate a rectal suppository dosage form from diuretic ethacrynic acid, which would add to the choice of treatment methods and thereby increase the possibilities of individual cure. On the other hand, the liberation and thereby the bioavailability of poorly-soluble ethacrynic acid needs to be enhanced, and for this purpose solubility-increasing additives new to rectal therapy were used. Solutol HS 15, Cremophor RH 40, and Cremophor RH 60 were used as additives in concentrations of 1, 3, 5, and 10%. The quantity of drug released changed as a function of additive concentration. Depending on the acceptor phase, the best results were achieved with an additive concentration of 1-3%, which is related to the optimal additive quantity accumulated on the boundary surface.

Biological Availability↗

PubMedDate not supplied

Cochlear vessel permeability to horseradish peroxidase after diuretic administration in the chinchilla.

The permeability of strial vessels to the small protein, HRP, was examined after administration of diuretics to determine if increased vascular permeability is a factor in the development of strial edema as it is in acoustic trauma. Chinchillas were injected with HRP and either ethacrynic acid, a loop-inhibiting diuretic, or mannitol, an osmotic diuretic. There was no increased vascular permeability to HRP. Therefore, unlike the increased vessel permeability of HRP seen after an acoustic insult, increased vessel permeability of HRP is not a factor in the formation of strial edema after either mannitol or ethacrynic acid administration.

Animals↗

PubMed1991

Regulation of renal hemodynamics after protein feeding: effects of loop diuretics.

These studies were designed to test the hypothesis that the renal vasodilation and increased glomerular filtration rate (GFR) after a high-protein meal are mediated by the tubuloglomerular feedback (TGF) mechanism. In eight chronically instrumented conscious dogs, a meal of raw beef (10 g/kg) caused GFR to increase from 66 +/- 5 to 90 +/- 7 ml/min and effective renal plasma flow (ERPF) to increase from 191 +/- 25 to 281 +/- 24 ml/min, while plasma alpha-amino N levels rose from 4.0 +/- 0.1 to 7.3 +/- 0.6 mg/dl. On another day the dogs were given an infusion of furosemide to block TGF, and fluid and salt losses were continuously replaced. Furosemide alone caused GFR to increase in most animals, although the average change did not reach statistical significance, and ERPF increased by 31%. Sodium excretion rose from 15 +/- 5 to 2,390 +/- 280 mueq/min, and urine flow rose from 1.17 +/- 0.22 to 20.5 +/- 2.4 ml/min. Autoregulatory capability was also abolished (autoregulatory index = 0.87 +/- 0.09 compared with 0.19 +/- 0.05 before furosemide). However, there was no significant change in GFR and ERPF after a subsequent meat meal in dogs receiving furosemide. On another day, some of the dogs were given another loop diuretic, ethacrynic acid, which caused no change in GFR, whereas its effects on ERPF, sodium excretion, and urine output were similar to those of furosemide. There were also no changes in GFR or ERPF after a meat meal during ethacrynic acid administration, despite normal increases in plasma alpha-amino N.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1982

Functional and morphological findings of endolymphatic sac.

After obliteration of endolymphatic sac and duct, no significant alteration in d.c. potential, K+ activity or protein content during the development of endolymphatic hydrops could be observed. The K+ activity of endolymphatic sac was only one-ninth of that in the cochlear part of the endolymph. After injection of Thorotrast into the endolymphatic sac, aggregated particles were found in the cochlear endolymph 2 days later. Ethacrynic acid (60 mg/kg) caused a decrease in K+ activity in the cochlear endolymph, but an increase in the endolymphatic sac. Intercellular edema was observed both in stria vascularis and in endolymphatic sac by light and electronmicroscopy after ethacrynic acid administration. These results suggest the existence of an active transport mechanism in the endolymphatic sac epithelium.

Animals↗

PubMedDate not supplied

Uptake of radioactive sulphur in the endolymphatic sac. An autoradiographic study.

Autoradiographic uptake of labelled sulphur (S35) in the endolymphatic sac was analysed after performing surgical labyrinthectomy and after systemic administration of glycerol and ethacrynic acid. Accumulation of radioactive substance was observed after surgical labyrinthectomy and associated with a deposition of stainable substance in the endolymphatic sac lumen. Increased activity was noted in the epithelial layer after administration of ethacrynic acid, whereas glycerol did not increase radioactivity in the endolymphatic sac despite the deposition of stainable substance therein. This fact was believed to depend on a too short time interval between the injection and the sacrifice of the animals, as well as a weaker concentration of the sulphated compound within the endolymphatic sac. The results suggest that the endolymphatic sac may secrete sulphur-containing substances presumably associated with a deposition of a stainable substance in the endolymphatic sac.

Animals↗

PubMed1987

[Protective effect on the brain of ion-blockers in experimental head injury].

It has been known that various derangements in ionic homeostasis develop following neural trauma. In particular, potassium efflux out of and calcium influx into the cells are thought to play important roles in causing cell damage. Concomitantly we have previously reported that increased extracellular potassium per se provoked by head injury induces convulsive seizure such that the sustained high extracellular potassium leads to animal death. The purpose of the present study was further to examine the beneficial effect of drugs which could inhibit such detrimental ion movements in experimental head injury. Awake male mice of dd-strain were restrained and subjected to head injury using a bakelite weight of 30 gm dropped from a height of 17.6 cm above the skull. This injury resulted in immediate loss of consciousness in 100%, convulsive seizure in about 70% and death in about 30% of animals. The severity of consciousness disturbance was evaluated by a pair of indices in time interval; time required for the recovery of righting reflex (RR) and for the recovery of spontaneous movement (SM). Ethacrynic acid, a loop diuretics, blocks carrier-mediated chloride transport into astroglia associated with sodium and water in the presence of high extracellular potassium. Animals were treated with either 0.5-1.0 mg/kg or 2.0-4.0 mg/kg of ethacrynic acid administered via tail vein 10 min before injury. In the other group of animals, a calcium entry blocker, flunarizine was injected intraperitoneally in doses 5, 10 and 20 mg/kg one hour pre-insult.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1975

Seasonal differences in drug- and temperature-dependent changes of the sodium transport across the isolated frog skin.

In two series of experiments, one conducted in the spring (May-June) and the other in the fall (September-November), the influence of raising temperature of the medium and of vasopressin, insulin and ethacrynic acid on polarized sodium transport in the epithelium of frog skin in vitro was studied. Net sodium transport was determined electrometrically, and active and passive components of transport by the isotope method. Raising temperature markedly increased both components, as well as net flux and electric potential of the membrane in the spring months, but not in the fall. Regardless of the character and extent of the effect on transport, raising temperature of the medium had no qualitative or quantitative influence on the action of vasopressin, insulin or ethacrynic acid.

Animals↗

PubMed1973

Effect of single dose administration of diuretics on the blood sugar of alloxan-diabetic mice or mice made hyperglycaemic by the acute administration of diazoxide.

1. Frusemide produced hyperglycaemia in mice when administered together with diazoxide. The interaction between the drugs in elevating the blood sugar was shown to be additive.2. The diuretic, natriuretic and kaliuretic effects of frusemide were very markedly attenuated by diazoxide.3. Neither ethacrynic acid nor hydrochlorothiazide exerted any effect upon blood sugar when administered together with diazoxide.4. Bilateral nephrectomy completely prevented the hyperglycaemic effect of frusemide in normal mice and in mice treated with diazoxide. Diazoxide itself still produced hyperglycaemia in nephrectomized mice.5. Frusemide, ethacrynic acid and diazoxide, but not hydrochlorothiazide, each produced hyperglycaemia in alloxan-diabetic mice, this being prevented by bilateral nephrectomy.

Animals↗

PubMed1977

Renal energy metabolism and sodium reabsorption after 2,4-dinitrophenol administration.

2,4-Dinitrophenol (DNP) (10 mg/kg body wt i.v.) increased renal cortical and outer medullary heat production rates and oxygen consumption by 70-90% in anesthetized dogs over a 90-min observation period without exerting any natriuretic effect. To examine whether DNP inhibited proximal reabsorption and increased distal delivery, ethacrynic acid (3 mg/kg body wt) was infused during maximal DNP effect. Sodium reabsorption fell by 14 +/- 6% in the cortex and 55 +/- 8% in the outer medulla, not significantly different from control experiments without DNP. Conversely, after ethacrynic acid administration, DNP had no additional natriuretic effect. Since DNP did not stimulate renal anaerobic metabolism (no lactate release), the effect of DNP was examined during hypoxia induced by intravenous infusion of NaCN (0.2 mumol/kg body wt-min) until renal metabolic rates fell. Subsequent infusion of DNP reduced tubular sodium reabsorption from 90 +/- 2 to 78 +/- 6%. Thus, DNP may raise renal metabolic rates by 70-90% without inhibiting sodium reabsorption, but, under conditions of hypoxia, DNP reduces sodium reabsorption and increases sodium excretion.

Anaerobiosis↗

PubMed2000

Phenobarbital increases DNA adduct and metabolites formed by ochratoxin A: role of CYP 2C9 and microsomal glutathione-S-transferase.

Ochratoxin A (OTA), a mycotoxin that induces nephrotoxicity and urinary tract tumors, is genotoxic and can be metabolized not only by different cytochromes P450 (CYP) but also by peroxidases involved in the arachidonic cascade, although the exact nature of the metabolites involved in the genotoxic process is still unknown. In order to establish the relation between OTA genotoxicity and the formation of metabolites, we chose three experimental models: kidney microsomes from rabbit, human bronchial epithelial cells, and microsomes from yeast that specifically express the human cytochrome P450 2C9 or 2B6 genes. OTA-DNA adducts were analyzed by (32)P postlabeling and the OTA derivatives formed were isolated by HPLC after incubation of OTA in the presence of: (1) kidney microsomes from rabbit pretreated or not with phenobarbital (PB); (2) human pulmonary epithelial cells simultaneously pretreated (or not) with PB alone or in the presence of ethacrynic acid (EA); (3) microsomes expressing CYP 2B6 and 2C9. PB pretreatment significantly increased DNA adducts formed after OTA treatment, both in the presence of kidney microsomes and bronchial epithelial cells, and induced the formation of new adducts. Ethacrynic acid, which inhibits microsomal glutathione-S-transferase, reduced DNA adduct level. DNA adducts were detected when OTA were incubated with microsomes expressing human CYP 2C9 but not with those expressing CYP 2B6. Several metabolites detected by HPLC were increased after PB treatment. Some of them could be related to DNA-adduct formation. In conclusion, OTA biotransformation, enhanced by PB pretreatment, increased DNA-adduct formation through pathways involving microsomal glutathion-S-transferase and CYP 2C9.

Animals↗

PubMed1976

Potassium flux in smooth muscle of frog stomach.

In frog stomach muscle fibers, normal steady-state K flux, estimated directly from 42K uptake, was 0.17 pmol/cm2 per s at 5 degrees C and 0.63 pmol/cm2 per s at 15 degrees C. Influx characteristics were studied at 5 degrees C, where backflux and diffusional delay effects are minimized. Steady-state K influx was a saturating function of external [K] over the range 0.25-11 mM [K]o; influx at normal and higher [K]o did not differ significantly. Na loading (in K-free or low K solution) strongly stimulated influx, which showed altered saturation kinetics; maximal K influx was a quasilinear function of internal [Na]. Ouabain (10(-4) M) reduced normal and stimulated K influx markedly. Ethacrynic acid (10(-3) M) caused net K loss and Na gain, but increased K influx fourfold; ouabain inhibited the stimulated influx by 50%. These results indicate that K influx depends mainly on cycling of the Na-K pump and is normally limited by Na efflux. Ethacrynic acid may stimulate another mode of pump operation, K-K exchange, and uncouple the normal operation.

Animals↗

PubMed2004

Effects of pH and the presence of micelles on the resolution of diuretics by reversed-phase liquid chromatography.

A comparative study on the performance of two RPLC modes on the separation of 18 diuretics with diverse acid-base behaviour (acetazolamide, althiazide, amiloride, bendroflumethiazide, benzthiazide, bumetanide, canrenoic acid, chlorothiazide, chlorthalidone, ethacrynic acid, furosemide, hydrochlorothiazide, piretanide, probenecid, spironolactone, triamterene, trichloromethiazide and xipamide) was carried out. A conventional octadecylsilane column and acidic acetonitrile-water mobile phases, in the absence and presence of micelles of the anionic surfactant sodium dodecyl sulphate (SDS), were used. The effects of pH and the modifiers acetonitrile and SDS on peak asymmetry, efficiency, selectivity, resolution and analysis time, were examined. The comparison of both RPLC modes (aqueous- and micellar-organics) was done using the same processing tools, applying several polynomial and mechanistic equations to describe the retention. The best separations were obtained by maximising the product of peak purities, considering a wide range of experimental conditions. The study illustrates that, despite the theoretical and practical complexity of the problem, the predicted optimal chromatograms can be reproduced experimentally with great accuracy. None of the examined RPLC modes was able to yield baseline separation of the 18 diuretics. However, their selectivity was complementary, being appropriate for different combinations of a smaller number of the assayed diuretics.

Chromatography, Liquid↗

PubMedDate not supplied

Detection of diuretics in horse urine by GC/MS.

The use of diuretics in horses subject to doping control is prohibited. Thus, a sensitive screening procedure is required to identify the chemically different diuretics. We communicate here a method to detect three commonly employed acidic diuretics: bumetanide, ethacrynic acid, and furosemide. A liquid-liquid extraction on Extrelut 3 was performed at weak acidic and basic conditions using ethyl acetate as organic solvent. For analysis by GC, the diuretics were methylated on-column in the presence of MSTFA/TMAH, avoiding the commonly employed highly toxic derivatizing agent methyl iodide. For identification of diuretics, we used a mass selective detector operating in the SIM (selected ion monitoring) mode. Confirmation analysis may be obtained with a full scan run. Recoveries for the individual drugs ranged from 31 to 48% at the 100-ng/mL level for 3 mL urine, using calibration curves of drug standards with linearity from 2.5 to 20 ng injected. The limit of detection amounts to 40 ng/mL for the three diuretics. The method permits rapid and sensitive detection of diuretics in horse urine and is recommended for doping control.

Animals↗

PubMed1986

Chloride transport inhibition by various types of loop diuretics in fish opercular epithelium.

Isolated opercular epithelia of killifish (Fundulus heteroclitus), mounted in an Ussing chamber, were used to study the effects of various diuretics on chloride transport, measured as short-circuit current (SCC). The acidic 'loop' diuretics, ethacrynic acid and azosemide, and the basic 'loop' diuretics, muzolimine and MK 447, reduced SCC and exhibited similar dose-effect curves, with EC50s for SCC of 64, 17, greater than 500 and 224 microM, respectively. The alkaline diuretic tizolemide (HOE 740) and the p-COOH-analogue of sulphanilamide were inactive, suggesting that the chloruretic effects of these agents are of a thiazide type. The method can thus discriminate between the effects of loop and thiazide types of diuretics, but not between those of structurally highly different 'loop' diuretics of an acidic and basic nature. Monomethylation of the SO2NH2 group of bumetanide had no effect on the activity of this agent whereas dimethylation reduced it fourfold. The (-)enantiomers of the 'loop' diuretics indacrinone and ozolinone were four and greater than 100 times more active, respectively, than the (+)forms. These results are in accordance with those obtained for the same drugs in the mammalian kidney, and point to the presence of a highly specific binding site for these diuretics. Attempts were also made to explore the prerequisites for binding of the loop diuretic to the active site. Pretreatment of the opercular epithelium with an alpha-L-fucose-binding lectin did not prevent the inhibitory actions of furosemide and indacrinone. Probenecid and (+)ozolinone, both of which block organic anion transport, did not prevent the effects of bumetanide and (-)ozolinone.

Animals↗